Both the intrinsic nerves and gut neuropeptides are known to regulate muscle contraction and relaxation in the small intestine. However, how nerves and peptides act together to regulate neuromuscular transmission is not well understood. The aim of this proposal is to define the neural and endocrine controls which regulate neuromuscular transmission in the rodent small intestine. Segments of duodenum and ileum are mounted in baths of Krebs solution gassed with 95% 0/2 - 5% Co/2 at 37/0 and stretched to optimal lengths. Each segment undergoes electrical field stimulation and the fluid bathing each segment is removed and assayed for vasoactive intestinal polypeptide (VIP), motilin, cholecystokinin, (CCK) and substance P. Atropine is used to study the effect of muscarinic blockade on neuropeptide release. Current amplitude during field stimulation is varied to selectively activate cholinergic excitatory nerves, non-cholinergic excitatory nerves, and non-cholinergic inhibitory nerves. A separate study examines the influence of neuropeptides and peptide antagonists or antisera on neuromuscular transmission. Circular and longitudinal muscle strips are stretched to optimal lengths and tensions are measured continuously. Resting and field-stimulated tensions are monitored as tissues are superfused with: 1) VIP, CCK, substance P, motilin, or met- and leu- enkephalin; 2) antisera to VIP, CCK, motilin, and substance P; 3) naloxone or proglumide. Current amplitude during field stimulation is varied to determine the effects of these agents on cholinergic excitatory nerves, non-cholinergic excitatory nerves, and non-cholinergic inhibitory nerves. Since preliminary observations suggest that current direction can preferentially activate excitatory or inhibitory nerves, a separate study examines the influence of directed electrical field stimulation applied at various current amplitudes on neuromuscular transmission. A final study examines enteric neuromuscular transmission in experimental diabetes mellitus. Neuropeptides release is studied in streptozotocin-treated rats, controls, and insulin-treated diabetic rats, while separate studies examine the effects of VIP, CCK, and motilin on enteric neuromuscular transmission in these animals. These experiments will help clarify the mechanism of neuropeptidergic transmission in the enteric nervous system. Ultimately, this study will help to better understand the pathophysiology of motor abnormalities such as intestinal pseudoobstruction, paralytic ileus, and diabetic enteropathy.